Practice Essentials
Eosinophilic fasciitis (EF), also called Shulman syndrome, is a rare, localized fibrosing disorder of the fascia. [1] The etiology and pathophysiology are unclear.
In 1974, Shulman provided an early description of eosinophilic fasciitis as a disorder characterized by peripheral eosinophilia and fasciitis that could be differentiated from scleroderma by the distinctive pattern of skin involvement that spares the digits, involves fascia rather than dermis, and is not accompanied by Raynaud phenomenon. [2, 3, 4]
Since 1974, over 300 patients with eosinophilic fasciitis have been reported. [5, 6] Despite this, the current understanding of the disease relies on a relatively few large case series and multiple case reports. Therefore, the understanding of key aspects of the disease continues to evolve.
The etiology of eosinophilic fasciitis remains unknown, although many possible triggers and disease associations have been suggested. Some aspects of pathophysiology have been elucidated; however, a more complete understanding has yet to develop.
The available literature has generated a broader clinical image of the condition, but fascial thickening in the setting of eosinophilia, elevated erythrocyte sedimentation rate, and hypergammaglobulinemia remain critical elements of the syndrome. Visceral involvement in eosinophilic fasciitis is generally absent, a finding that helps differentiate eosinophilic fasciitis from systemic sclerosis and other differential considerations. However, an association with several hematologic diseases is recognized and frequently carries a grave prognosis.
The diagnosis of eosinophilic fasciitis is suspected in a patient presenting with characteristic skin changes and consistent laboratory findings. It is confirmed with full-thickness biopsy or characteristic MRI findings. See Presentation and Workup.
Eosinophilic fasciitis is generally corticosteroid-responsive, and initial treatment regimens are based on this therapy. Multiple additional agents have been used in steroid-refractory disease. The evidence for many of these agents is anecdotal, and there is no general consensus regarding the best agent for treatment of steroid-resistant disease or cases refractory to steroid withdrawal. See Treatment and Medication.
See also Dermatologic Manifestations of Eosinophilic Fasciitis.
Pathophysiology
Although the etiology of eosinophilic fasciitis is unknown, studies have shed light on some of the mechanisms involved in its pathogenesis.
In general, the pathophysiology underlying eosinophilic fasciitis is postulated to involve an inflammatory response resulting in an activated inflammatory cell infiltrate of affected tissues and subsequent dysregulation of extracellular matrix production by lesional fibroblasts.
Viallard et al demonstrated that, when stimulated, peripheral blood mononuclear cells of eosinophilic fasciitis patients produce significantly higher amounts of five cytokines, including interleukin (IL)–5 and interferon (IFN)–gamma. [7] IL-5 is known to activate mature eosinophils and to stimulate eosinophil chemotaxis, growth, and differentiation. IFN-gamma activates tissue macrophages and T cells. The findings of Dziadzio et al support increased levels of IL-5 in eosinophilic fasciitis, in addition to increased levels of transforming growth factor (TGF)–beta, another fibrogenic cytokine. [8]
Toquet et al investigated the phenotype of the lesional inflammatory cell infiltrate in patients with eosinophilic fasciitis and demonstrated a predominance of macrophages, CD8+ lymphocytes, and few eosinophils. [9] Pathologic specimens from patients with eosinophilic fasciitis demonstrate increased numbers of eosinophils, especially early in the disease course.
Taken together, the findings of these studies suggest a mechanistic framework marked by a proinflammatory and fibrogenic cytokine response with resultant tissue inflammatory cell infiltration.
In the tissues, the end effector cell of fibrosis is the fibroblast. Fibroblasts from lesional tissue of patients with eosinophilic fasciitis produce excess collagen in vitro and display elevated TGF-beta and type 1 collagen mRNA levels when examined via in situ hybridization with specific cDNA. [10, 11] Therefore, the pathogenesis appears to involve the concomitant increase in the expression of genes for TGF-beta and extracellular matrix proteins in fibroblasts in the affected tissues.
Mori et al suggested that an autocrine stimulatory loop involving major basic protein, a product of eosinophil degranulation, IL-6, which enhances collagen production and is induced my major basic protein, and TGF-beta could account for the progressive fibrosis seen in several eosinophil prominent disorders. [12]
Other studies showed elevated levels of serum manganese superoxide dismutase and tissue metalloproteinase 1 (TIMP-1) in eosinophilic fasciitis, suggesting a role in pathogenesis and providing a possible marker of disease activity. [13]
Fasciitis may be a common manifestation of various pathophysiologic processes associated with eosinophilia. The existence of primary and secondary forms of fasciitis has recently been suggested.
Understanding the mechanisms involved in the development of fascial inflammation and fibrosis in these conditions may yield insights into the pathogenesis of other fibrotic skin diseases.
Etiology
The etiology of eosinophilic fasciitis is unknown. Its clinical manifestations are the result of an inflammatory response in the affected tissues. As explained above, the current understanding of eosinophilic fasciitis relies on a relatively few case series and case reports. As such, many etiologic factors have been suggested with varying degrees of supporting evidence. Any of these factors, alone or in combination, may possibly initiate this inflammatory response.
Several possible triggers have been reported with some consistency. A preceding history of vigorous exercise or trauma has been reported in 30%-50% of patients. [14, 15] Multiple drugs have also been implicated, including simvastatin, atorvastatin, and phenytoin. [16, 17, 18] A number of cases of eosinophilic fascitis following treatment with immunne checkpoint inhibitors atezolizumab, nivolumab and pembrolizumab have been reported. One report described eosinophilic fasciitis in association with cemiplimab. [19]
Several cases have demonstrated positive Borrelia serologies. The significance of this finding continues to be debated. Spirochetes were visualized by silver stain in 4 patients in one study. [20] These findings have not been repeated. It has been suggested that positive serology for Borrelia represents an epiphenomenon among cases from Borrelia-endemic areas and is insufficient evidence of infection and therefore does not support a causal association. [21]
Eosinophilic fasciitis shares clinical similarities, as well as key differences, with eosinophilia-myalgia syndrome. Some studies have suggested an association between l-tryptophan ingestion and eosinophilic fasciitis. [22, 23] Despite this, there is no consistent association between l-tryptophan or other dietary exposure and eosinophilic fasciitis. As evidence, l-tryptophan use was significantly associated with dyspnea, an uncommon finding in eosinophilic fasciitis cases. In another instance, a patient with eosinophilic fasciitis had used l-tryptophan for several years but had started a formal exercise program 2 weeks prior to disease onset.
Multiple additional etiologic triggers have been suggested by single or infrequent case reports.
As with etiology, eosinophilic fasciitis has been associated with several diseases. [24]
Hematologic diseases have been consistently reported and are supported by large case series and case reports. [14, 15, 25] The spectrum of associated hematologic disease is broad and includes aplastic and hemolytic anemia, thrombocytopenia, myeloproliferative disorders, myelodysplastic disorders, lymphoma, leukemia, monoclonal gammopathy of undetermined significance (MGUS), and multiple myeloma. [25, 26, 27]
An association with thyroid disease has been reported in several cases. [28] Eosinophilic fasciitis has rarely been linked to solid-organ tumors and primary biliary cirrhosis, in addition to several other diseases. These disease associations may suggest a shared pathophysiology of cellular dysregulation and/or autoimmunity.
Epidemiology
Frequency
United States
Eosinophilic fasciitis is very rare.
Mortality/Morbidity
No data are available on morbidity or mortality rates associated with eosinophilic fasciitis. Morbidity may result from joint contractures or carpal tunnel syndrome associated with fascial fibrosis. Rarely, a fatal aplastic anemia may develop.
Race-, sex-, and age-related demographics
Eosinophilic fasciitis affects whites more often than it affects other races. It has been reported in African Americans, Africans, and Asians. [29, 30, 31, 32, 33]
In adults, eosinophilic fasciitis affects women more often than men. [14, 34, 15]
The age range in eosinophilic fasciitis is 1-88 years, although most patients present during the third to sixth decades of life. [34] The average age of onset in two case series was 54.4 and 49.8 years. [34, 15]
Prognosis
A retrospective review found that clinical factors associated with persistent fibrosis included presence of morphealike skin lesions, younger age at onset, truncal involvement, and presence of dermal fibrosclerosis on histopathologic specimen. [5]
Loss of edema is usually the first clinical sign of improvement and can occur within 4 weeks of commencing treatment. Concurrently, the skin becomes softer, but 3-6 months may elapse before maximal reduction in induration and contractures is achieved. [14, 15]
While total resolution of the clinical signs can occur, some degree of induration remaining even after many months of corticosteroid therapy is not unusual.
A direct correlation does not always exist between clinical disease activity and laboratory findings. The eosinophil count and ESR usually return to reference ranges within 6-8 weeks, although the ESR prolongation and hypergammaglobulinemia may persist for up to 12 months. [14, 15]
Eventually, corticosteroid therapy can be withdrawn in many patients, without relapse occurring.
The development of aplastic anemia is a rare but grave complication. [35] One study reported on 4 patients with eosinophilic fasciitis and severe aplastic anemia. In 3 cases, the aplastic anemia was refractory to conventional immunosuppressive therapy with antithymocyte globulin and cyclosporine. However, in 1 patient, rituximab displayed significant efficacy for both the skin and hematologic symptoms. In an additional 19 cases of eosinophilic fasciitis and aplastic anemia, corticosteroid regimens improved skin symptoms in 5 of 12 cases but were ineffective in the treatment of aplastic anemia in all but 1 case. Aplastic anemia was profound in 13 cases and was the cause of death in 8 cases. Only 5 patients achieved long-term remission. [36]
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Eosinophilic fasciitis. The arm of this patient demonstrates the puckered, so-called orange-peel or cobblestone skin that may occur in eosinophilic fasciitis.
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Eosinophilic fasciitis. The skin of the patient's back appears shiny due to the stretched dermis overlying an inflamed fascia. Mild diffuse hyperpigmentation is present, along with a U-shaped area of hypopigmentation extending approximately from T10 to L4.
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Eosinophilic fasciitis. The skin of the abdomen and breasts is shiny and taut. The thigh reveals puckering or cobblestoning of the overlying dermis due to scattered retraction from scarred fascia.
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Eosinophilic fasciitis. Top: In this gross specimen, the dermis (A), subcutaneous adipose tissue (B), and skeletal muscle do not appear unusual. However, the fascia (D) is markedly thickened. Bottom left: The gross findings are recapitulated in this low-power photomicrograph. The epidermis, dermis (A), and subcutaneous adipose tissue are not remarkable in this case. The fascia (D) is markedly thickened and focally infiltrated by inflammatory cells (E). The small amount of skeletal muscle (C) appears normal (hematoxylin and eosin stain at low power). Bottom right: A close-up photograph of a portion of the fascia showing mostly edematous cellular connective tissue (F). It is focally infiltrated by inflammatory cells, including lymphocytes, plasma cells, and histiocytes. The more intensely stained hypocellular pink bands across the top of the field (G) are part of an interstitial exudate of fibrin (hematoxylin and eosin stain at medium power).
